Ili-axnhr

ABSTRACT

1. THE PROCESS OF REDUCING APPETITE WHICH COMPRISES ADMINISTERING TO ANIMALS IN NEED THEREOF AN APPETITE REDUCING AMOUNT OF N-BENZYL-B-METHOXY-B-(3-TRIFLUOROMETYL) PHENETHYLAMINE OR A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF.

United States Patent 28,229 fl-ALKOXY-TRIFLUOROMETHYLPHEN- ALKYLAMINESJohn A. Faust, Solvang, and Melville Sahyun, Santa Barbara, Calif.; saidFaust assignor to said Sahyun, dcoilng business as Sahyun Laboratories,Santa Barbara,

No Drawing. Original No. 3,459,803, dated Aug. 5, 1969,

Ser. No. 666,457, Sept. 8, 1967, which is a continuationin-part of Ser.No. 467,759, June 28, 1965. Application for reissue July 28, 1970, Ser.No. 59,042, now reissue Patent No. 27,551, dated Jan. 16, 1973. Dividedand this application for reissue Oct. 12, 1972, Ser. No.

Int. Cl. A61k 27/00 US. Cl. 424-330 1 Claim Matter enclosed in heavybrackets [fl appears in the original patent but forms no part of thisreissue specification; matter printed in italics indicates the additionsmade by reissue.

ABSTRACT OF THE DISCLOSURE Alkoxy-trifluoromethylphenalkyl amines usefulto reduce nausea and to depress appetite [Z] and the process of reducingappetite by the administration of a lower-alkoxy substitutedtrifluoromelhylphenalkyl secondary amine.

This application is a division of Ser. No. 59,042 filed July 28, 1970,which is an application for reissue of U.S. Pat. No. 3,459,803, now US.Pat. No. Re. 27,551.

This invention relates to novel secondary amines, more particularly tolower-alkoxy-substituted trifluoromethylphenalkyl secondary amines.

This application is a continuation-in-part of application S.N. 467,759,filed June 28, 1965 and now abandoned.

The composition aspect of this invention resides in the concept oflower-alkoxy-substituted trifiuoromethylphenalkyl secondary amines.

The process of use aspect of this invention resides in the concept ofadministering a lower-alkoxy-substituted trifluoromethylphenalkylsecondary amine in a pharmaceutically acceptable form to mammaliananimals to reduce nausea.

Another process of use aspect of this invention resides in the conceptof administering a lower-alkoxy-substituted trifiuoromethylphenalkylsecondary amine in a pharmaceutically acceptable form to mammaliananimals to re duce appetite.

The phenalkylamines of this invention can be represented by the formulaO-lowcr alkyl II- A NH R wherein R is hydroxyethylene or hydrocarboncontaining 1-8 carbon atoms, preferably lower-alkyl, and A is a 1-3carbon atom alkylene bridge, containing a total of 1-8 carbon atoms,joining the loWer-alkoxy group-bearing carbon atom and the aminenitrogen atom, e.g., methylene, ethylene and trimethylene, any of whosecarbon atoms can bear one or more alkyl groups so as to contain up to atotal of 8 carbon atoms, preferably methylene with or without a methylgroup. Especially preferred are each of the above whose C1 group is inthe metaposition.

As used herein, the term hydrocarb0n" includes alkyl, e.g., methyl,ethyl, octyl, alkenyl, e.g. allyl, alkynyl, aryl,

Re. 28,229 Reissued Nov. 5, 1974 e.g., phenyl, alkaryl, e.g., tolyl,aralkyl, e.g., benzyl, phenethyl, cycloalkyl, e.g., cyclopropyl,cyclopentyl, cyclohcxyl, cyclohexylmethyl and cycloalkenyl, e.g.,cyclohexenyl. Preferred are the saturated hydrocarbon of e.g., alkyl,cycloalkyl, alkylcycloalkyl and cycloalkylalkyl, especially cycloalkyland alkyl.

As used herein the terms lower-alkyl" and loweralkoxy referrespectively, to alkyl and alkoxy groups containing from one to eightcarbon atoms, preferably less than five carbon atoms, which can bestraight-chain or branched. Representative alkyl radicals are methyl,ethyl, propyl, isopropyl, n-butyl and sec-butyl, amyl, isoamyl, hexyl,heptyl and octyl. Representative lower-alkoxy radicals are methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, and sec-butoxy, amyloxy andoctyloxy.

Racemic mixtures are obtained as the carbon atom which bears the ethersubstituent and which is attached to the benzene ring is asymmetric.Also, when a carbon atom in the methylene chain is asymmetric, a furtherracemate mixture is possible. Racemate pairs can be separated byfractional crystallization of an acid addition salt and each d and lisomer can be separated from the racemate in the conventional manner.

The compounds of this invention comprise the acid addition salts. Whenthe tangible embodiments of the invention are employed for theirpharmacological effect, they ordinarily will be used in the form ofnontoxic acid addition salts, i.e., pharmaceutically acceptable salts.However, any acid addition comes within the scope of this inveniton asthey are all useful, e.g., for purifying the free base or for separatingracemate mixtures.

Suitable non-toxic, i.e., pharmaceutically acceptable, acid additionsalts are those formed from mineral acids, e.g., hydrochloric acid,hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid andsulfuric acid, and organic acids, e.g., acetic acid, citric acid,tartaric acid, lactic acid, and the like, which provide thehydrochloride, hydrobromide, hydroiodide, nitrate, phosphate or acidphosphate, sulfate or bisulfate, acetate, citrate or acid citrate,tartrate or bitartrate, and the lactate salts, respectively.

Equivalents of the compounds of this invention are those of the aboveformula bearing additional simple substituents on the benzene ring ofthe molecule, e.g., one, two or more of lower-alkyl, aryl, alkaryl,halo, including, chloro and bromo, trifluoromethyl, hydroxy, nitro,etc., in the 2,4,5, or 6-position.

Preferred of the compounds of this invention are those wherein theN-lower-alkyl group is methyl or ethyl, the lower-alkoxy group ismethoxy or ethoxy, and the methylene bridge contains one or at most twocarbon atoms, i.e., the alpha-unsubstituted and alpha-methyl-phenethylcompounds, and those having combinations of these preferred groups,e.g., N,m di-methyl-beta-methoXy-m-trifluoromethylphenethylamine,N-methyl-beta-methoxy-m-trifiuoromethylphenethylamine, Nmethyl-beta-ethoxy-m-trifluoromethylphenethylamine, Nethyl-beta-methoxy-m-trifluoromethylphenethylamine, andN-ethyl-beta-ethoxy-mtrifluoromethylphenethylamine.

The following is the manner and process of making and using theinvention and the best mode contemplated ofcarrying out the invention.

The compounds of this invention can be prepared by first converting atrifluoromcthyl substituted phenyl bromide to the corresponding Grignardreagent.

The magnesium Grignard reagent is then reacted with a lower-alkyl0:,w-dih2liO-i0Wfif-flikYl ether to form a trifluoromethylphenalkylhalide bearing a lower-alkoxy group on the carbon atom alpha to thephenyl ring. Displacement of the halogen atom by reaction with a primaryamine produces the compounds of this invention.

These reactions can be illustrated by the following formulae:

O-lower alkyl L'lgBr H AX -lower alkyl RNI-I I r or. or,

II III O-lower alkyl H -.ANHR

A and R having the value given above and X is Cl or Br.

The compounds of this invention possess anti-emetic, anti-tussive andanorexic activities. In addition, they exhibit some CNS elTects,manifested primarily as depressant, e.g., sedative activities, in mostspecies usually at doses higher than that required to obtain anti-emeticor anorexic activity. Mydriasis is also produced at high dosage levels.They are nicotine antagonists and protect at low oral doses againstotherwise fatal doses of nicotine. The combination of anti-emetic andanti-tussive activities is unusual in phenethylamines, whether theii-methylene carbon atom is unsubstituted or substituted with hydroxy oralkoxy. Similarly, phenethylamines known to possess anti-emeticactivity, e.g., the amphetamines, also undesirably produce CNSstimulation, e.g., pressor, eflects.

The compounds of this invention can be administered orally,subcutaneously, intravenously, intraperitoneally, etc., in the usualpharmaceutical forms, e.g., admixed with pharmaceutical excipients inthe form appropriate, e.g., tablets, capsules, suppositories, in liquidemulsions, solutions, suspensions, etc. Their intravenous andintramuscular anti-emetic activity is particularly valuable because ofthe difiiculty in orally administering drugs in cases of extreme nausea.The selected compound generally should be present in a concentrationwhich will provide at least about 1 mg. per unit dosage, i.e., pertablet, capsule, teaspoonful, etc. The usual I.M. oral dose is about 0.1to 2.0 mg./kg. or more, up to about mg./kg. About or more times thisdosage can be administered to laboratory test animals for test purposes.Effective LP. and oral dosages are about 1.5-10 times these amounts.

The following preparations and examples are illustrative of thecompounds of this invention and of the processes by which they can beprepared. Temperatures are given in degrees centigrade.

PREPARATION l Beta-methoxy-3-trifluoromethyl-phenyl bromide To a stirredsolution of the Grignard reagent prepared from 124 grams (0.5 mole) of3-bromo-alpha, alpha, alpha-trifluorotoluene and 14 grams (0.57 mole) ofmagnesium in 500 milliliters of anhydrous ether was added an ethersolution of 109 grams (0.5 mole) of alpha, betadibromoethyl methylether. The homogeneous reaction mixture was allowed to remain overnightat degrees and was then refluxed for 6 hours. The mixture was pouredinto iced dilute hydrochloric acid. The ether layer was separated,washed, dried and distilled. The yield of betamethoxy3-trifluoromethyl-phenethyl bromide was 125 grams (80 percent), B.P.8287 C./1.7 mm.; 119-120 C./20 mm.

PREPARATION 2 Beta-ethoxy-3-trifluoromethyl-phenethy1 bromide Thereaction of 0.3 mole of alpha, beta-dibromoethyl ethyl ether with 0.33mole of 3-trifiuoromethyl-phenyl magnesium bromide according to themethod of Preparation 1 gave on distillation 60 grams (67 percent) ofbetaethoxy-3-trifluoro-methyl-phenethyl bromide, B.P. 8890 C./ 0.2 mm.

In the same manner, beta-n-butoxy-3-trifluoromethylphenethyl bromide isprepared from alpha, beta-dibromoethyl-n-butyl-ether.

Following the procedure of Preparation 1,beta-metboxy-4drifluoromethyl-phenethylbromide and otherbetalower-alkoxy-4-trifluoromethylphenethyl bromides are prepared by thereaction of 4-trifluoromethylphenethyl magnesium bromide with alpha,beta-dibromoethyl ethyl ether and other alpha, beta-dibromoethyllower-alkyl ethers. The correspondingbeta-methoxy-2-trifluoromethylphenethyl bromide and otherbeta-lower-alkoxy-2-trilluoromethylphenethyl bromides are similarlyprepared using Z-trifluoromethylphenyl magnesium bromide. Thealpha-alkyl-beta-lower alkoxy-2-, 3- and 4-trifluoromethylphenethylbromides are prepared by employing the appropriatealpha-beta-dihalo-lower-alkyl ether.

Example 1.N-methyl-;3-methoxy-;9-(3-triflouromethyl) phenethylaminehydrochloride A mixture of g. (0.14 mole) offi-methoxy-3-trifluoromethylphenethyl bromide, 40 g. (1.3 mole) ofmonomethylamine and 400 ml. of isopropyl alcohol, contained in apressure vessel, was heated at 65 for 24 hours. The excess methylamineand alcohol were removed by distillation, and the residue waspartitioned between dilute hydrochloric acid and ether. The aqueoussolution was made alkaline with sodium hydroxide and the liberated oilybase was extracted with ether. Distillation of the dried ether solutionyielded 18.6 g. (57 percent) of N-methylfl-methoxy )8(3-trifluoromethyl)phenethylamine, B.P. 113-117 (21 mm.).

Analysis.Calculated for C H F NO: N, 6.00; Neut. Equiv., 233. Found: N,5.50; Neut. Equiv., 240.

The hydrochloride, prepared in ether and recrystallized from a mixtureof isopropyl alcohol and ether, melted at 195-196.

Analysis-Calculated for C H F NO'HCl: N, 5.19; Cl, 13.14. Found: N,5.00; Cl 13.56.

Example 2.-N-methyl-;3-methoxy-B-(2trifiuoromethyl) phenethylaminehydrochloride (a) 8 Methoxy 9 (Z-trifluoromethyl)phenethyl bromide-Tothe Grignard reagent, prepared from 22.5 g. (0.01 mole) of commercialo-bromobenzotrifiuoride and 2.4 g. (0.1 g. at.) of magnesium in ether,there was added, dropwise at 25, an ether solution of 21.8 g. (0.1 mole)of a,;8-dibromoethyl-methyl ether. (J. Am. Chem. Soc. 52, 651 (1930);J.C.S. 1942, 520.) The reaction caused the ether to reflux, andrefluxing was continued for one hour after the addition. The cooledsolution was poured over iced hydrochloric acid and the ether layer wasseparated, washed with water, dried and distilled to yield 15.6 g. (55percent) of }8-methoxy- B (Z-trifluoromethyl)phenethyl bromide, B.P.7175 (0.5 mm).

(b) N-methyl-B-methoxy-fl- 2-trifluoromethyl phenethylaminehydrochloride.A solution of 11.8 g. (0.042 mole) ofB-methoxy-fi-(2-trifluoromethyl)phenethyl bromide in 75 ml. of isopropylalcohol containing 16 g. (0.5 mole) of methyl amine was heated, in apressure bottle, at C. for 44 hours. The cooled solution was distilledto remove the excess methylamine and isopropyl alcohol and the residuewas partitioned between dilute hydrochloric acid and ether. The aqueoussolution was made alkaline and the liberated base was extracted withether and distilled. Yield, 3.3 g. (34 percent) of N-methyl-fl-methoxyfl(2 trifluoromethyl)phenethylamine, B.P. 113-115" (22 mm.).

Analysis.Calculated for C H F NO: N, 6.01; Neut. Equiv., 233. Found: N,5.68; Neut. Equiv., 235.

The hydrochloride, prepared in ether with ethereal hy-i drogen chloride,melted at 257-258 after recrystallization from methanol-ether.

Analysis-Calculated for ,C H F NO-HCI: N, 5.19; Cl-, 13.15. Found: N,4.80; CI, 13.60.

Example 3.-N-n1ethyl-fl-methoxy-fl-(4-trifluoromethyl)phenethylaminehydrochloride (a) [3- Methoxy-B- (4-trifluoromethyl phenyl bromide- Thiscompound was prepared in the same manner as the corresponding2-trifluoromethyl compound as described in Example 2a. From 0.1 mole ofp-bromobenzotrifluoridc there was obtained 16.8 g. (72 percent) offl-methoxy-fi- (4-trifluoromethyl)phenyl bromide, B.P. 71-75 (0.5 mm.).

(b) N-methyl-fi-methoxy-fi-M trifluoromethyl)phenethylaminehydrochloride.A heterogenous mixture of 16.8 g. (0.06 mole) of the bromocompound of Example 2a and 92 g. (1.2 mmole) of 40 percent aqueousmethylamine was heated at 50-55" in a pressure bottle. for 64 hours. Theexcess methylamine was removed by distillation, and the residue waspartitioned between dilute hydrochloric acid and ether. The aqueoussolution was made alkaline, and the liberated base was extracted withether and distilled. Yield, 3.4 g. (24 percent) of N-methyl-B-methoxy-B-(4-trifiuoromethyl)phenethylamine, B.P. 120- 122 (20 mm.).

The hydrochloride, prepared in ether with ethereal hydrogen chloride,melted at 233-234 after recrystallization from a mixture of ethanol andether.

Analysis-Calculated for C H F NO-Hcl: N, 5.19; CL", 13.15. Found: N,4.66; CIr, 12.92.

(0.12 g. at.) of magnesium in ether, there was added dropwise an ethersolution of the above dichloro compound. Stirring and refluxing werecontinued for one hour after the addition, after which the mixture waspoured over iced hydrochloric acid. The ether layer was separated, driedand fractionally distilled to yield 17.3 g. (57 percent) of'ymethoxy-'y-(3-trifiuoromethyl)phenylpropyl chloride, B.P. 8285 (0.5mm.).

(c) N-methyl-y-methoxy- -(3-trifluoromethylphenyl) propylaminehydrochloride.An autoclave was charged with 175 ml. of isopropyl alcoholcontaining 31 g. (1 mole) of methylamine and 17.3 g. (0.068 mole) of theabove chloro-ether. The temperature of the mixture was maintained at95-100 for 14 hours, after which the solution was distilled to removethe excess methylamine and he solvent. The residue was partitionedbetween dilute aydrochloric acid and ether, and the aqueous solution wasrendered alkaline. The liberated base was isolated by ether extractionand distilled. Yield, 9 g. (54 percent) of N-methyl-'ymethoxy-'y-( 3trifluoromethylphenyl)propylamine, B.P. 126-128 mm.).

Analysis.Calculated for C H F NO: N, 5.67; Neut. Equiv., 247. Found: N,5.32; Neut. Equiv., 238.

The hydrochloride, prepared in ether with hydrogen chloride, melted at111-112" after recrystallization from a mixture of ethanol and ether.

Analysis.Calculated for C H F NO-HCl: N, 4.94, CI-, 12.45. Found: N,4.81; Cl, 12.71.

Following the procedure of Example 1, the following compounds wereprepared by substituting the appropriate amine for the methylamine inthe alkylation reaction 13.1. (base) M.P. (111, R" A R (mm.) HCl) In HCH1 Cal-I 122-4/20 1 189-190 m H CH: CiHn 145-7/20 138-139 m H CH,CH(CH3): 155-157 m H CH CH CH=CIh 146-147 m H CH CHICIIqOH 3 152-153 m HCH, Cyclohexyl 106-9/0. 2 140-141 m H CH Benzyl 135-7/0. 3 165-167 m HCH, Phenethyl 3 17lH71 m H CH1 CI m H CH: CHzCIIiOH 34 /0. m H CH1 H;134-8/20 m H CIMCHs) CH3 110-20/23 1 165-166 m H CH1 Cyclopentyl 6144-145 In H CH C(CHa): 125-28/26 1 235-2345 p H CH Cycle entyl 1188-180 p H CH Cyclo exyl 224-225 In p-CHaO CH: CH; 11tH2/0. 1 183-184In p-CH O CH1 CIflCHs); 2 187-189 5 2-CH3O CH1 CH5 146-147 5 2-CH O CH1CHtClh): 115-17/0. 5 1 200-201 1 Reeryst. isopropyl alcohol-ether.

2 Reeryst. acetone-ether.

8 Recryst. acetone.

1 Reeryst. ethanolether.

i Recryst. benzene-pet. ether.

Example 4.-N-methyl-- -methoxy-'y-(3-trifluorornethylphenyl) propylaminehydrochloride A related invention are the primary amines otherwisecorresponding to the secondary amines described herein, i.e., thoserepresented by Formula I wherein R is hydrogen. These compounds alsopossess pharmacological activity, including CNS depressant activity.They are also useful as intermediates in the production of thecorresponding secondary amines of this invention by alkylation with anappropriate hydrocarbon halide or with ethylene oxide. The followingexample is representative of the manner of producing these primaryamines by the reaction of the correspondinglower-alkoxy-trifiuoromethylphenylalkyl halide with ammonia.

fl-methoxy-p-(m-trifluoromethyl) phenethylamine hydrochloride Twenty-twograms (0.078 mole) of fl-methoxy-B-(mtrifluoromethy1)phenethyl bromidewas combined with 400 ml. of methanol which had been saturated withammonia at 10. The solution, contained in an autoclave was heated to80-90" for 5 hours and cooled. The alcohol was removed by distillationand the residue was partitioned between dilute sodium hydroxide andether. The ether solution was washed, dried and distilled to yield 13.2g. (77 percent) of fi-methoxy-B-(m-trifiuoromethyl)phenethylamine; B.P.110-1l8 (22 mm.). The hydrochloride, prepared in ether andrecrystallized from isopropyl alcoholether, melted at 168-169".

Arialysis.-Calculated for C H F NOHCl: N, 5.48; C1 13.88. Found: N,5.46; Cl-, 13.94.

What is claimed is:

1. The process of reducing appetite which comprises administering toanimals in need thereof an appetite re ducing amount ofN-benzyl-B-methoxy-fl-(3-trifluor0- methyl)phenethylamine or apharmaceutically acceptable acid addition salt thereof.

References Cited The following references, cited by the Examiner, are ofrecord in the patented file of this patent or the original patent.

8 UNITED STATES PATENTS 10/1966 Mills 260-5706 2/1963 Weinstock 260-3499/ 1964 Huebner 260-41265 12/1965 Sahyun et a1. 260-5706 OTHERREFERENCES Madinaveitia, Chemical Abstracts 16:92 (1922). Madinaveitia,Chemical Abstracts 16: 1946-47 (1922). F005 et al., Chemical Abstracts59: 1610-11 (1963). Steinberg et al., J. Org. Chem., vol. 13, p. 413(1948). Kaye et al., J. American Chem. Soc., 73:48935 (1951). ChemicalAbstracts 67:64023A (1967).

Wilson et al., Textbook of Organic Medicinal & Phar- 15 maceuticalChemistry 1962, pp. 388-389, 396397 ALBERT T. MEYERS, Primary ExaminerN. A. DREZIN, Assistant Examiner US. Cl. X.R.

1. THE PROCESS OF REDUCING APPETITE WHICH COMPRISES ADMINISTERING TOANIMALS IN NEED THEREOF AN APPETITE REDUCING AMOUNT OFN-BENZYL-B-METHOXY-B-(3-TRIFLUOROMETYL) PHENETHYLAMINE OR APHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF.